tbuckley/cabot-search huggingface dataset:
Challenges in Estimating the Effectiveness of COVID-19 Vaccination Using Observational Data
Authors: William J. Hulme, Elizabeth Williamson, Elsie M.F. Horne, Amelia Green, Helen I. McDonald, Alex J. Walker, Helen J. Curtis, Caroline E. Morton, Brian MacKenna, Richard Croker, Amir Mehrkar, Seb Bacon, David Evans, Peter Inglesby, Simon Davy, Krishnan Bhaskaran, Anna Schultze, Christopher T. Rentsch, Laurie Tomlinson, Ian J. Douglas, Stephen J.W. Evans, Liam Smeeth, Tom Palmer, Ben Goldacre, Miguel A. Hernán, Jonathan A.C. Sterne
Journal: Annals of Internal Medicine (2023)

The COVID-19 vaccines were developed and rigorously evaluated in randomized trials during 2020. However, important questions, such as the magnitude and duration of protection, their effectiveness against new virus variants, and the effectiveness of booster vaccination, could not be answered by randomized trials and have therefore been addressed in observational studies. Analyses of observational data can be biased because of confounding and because of inadequate design that does not consider the evolution of the pandemic over time and the rapid uptake of vaccination. Emulating a hypothetical "target trial" using observational data assembled during vaccine rollouts can help manage such potential sources of bias. This article describes 2 approaches to target trial emulation. In the sequential approach, on each day, eligible persons who have not yet been vaccinated are matched to a vaccinated person. The single-trial approach sets a single baseline at the start of the rollout and considers vaccination as a time-varying variable. The nature of the confounding depends on the analysis strategy: Estimating "per-protocol" effects (accounting for vaccination of initially unvaccinated persons after baseline) may require adjustment for both baseline and "time-varying" confounders. These issues are illustrated by using observational data from 2 780 931 persons in the United Kingdom aged 70 years or older to estimate the effect of a first dose of a COVID-19 vaccine. Addressing the issues discussed in this article should help authors of observational studies provide robust evidence to guide clinical and policy decisions.
KDIGO provided recommendations on SGLT2 inhibitors and nonsteroidal MRAs in patients with diabetes and CKD
Authors: Matthew van Norman, Donald A. Molony
Journal: Annals of Internal Medicine (2023)

Source Citation Navaneethan SD, Zoungas S, Caramori ML, et al. Diabetes management in chronic kidney disease: synopsis of the KDIGO 2022 clinical practice guideline update. Ann Intern Med. 2023;176:381-387. 36623286
In <i>H pylori</i> infection, vonoprazan plus high-dose amoxicillin was noninferior to B-quadruple therapy for eradication
Authors: Duncan J. Flynn, Joseph D. Feuerstein
Journal: Annals of Internal Medicine (2023)

Source Citation Qian HS, Li WJ, Dang YN, et al. Ten-day vonoprazan-amoxicillin dual therapy as a first-line treatment of Helicobacter pylori infection compared with bismuth-containing quadruple therapy. Am J Gastroenterol. 2023;118:627-634. 36729890
Phase II Randomized Trial of Lenalidomide in Children With Pilocytic Astrocytomas and Optic Pathway Gliomas: A Report From the Children's Oncology Group
Authors: Katherine E. Warren, Gilbert Vezina, Mark Krailo, Linda Springer, Allen Buxton, Cody J. Peer, William D. Figg, Chris William-Hughes, Sandy Kessel, Maryam Fouladi, Amar Gajjar, Daniel Bowers
Journal: Journal of Clinical Oncology (2023)

PURPOSE Children with low-grade glioma often require long-term therapy and suffer from treatment morbidity. Although targeted agents are promising, tumor targets often encompass normal developmental pathways and long-term effects of inhibition are unknown. Lenalidomide is an immunomodulatory agent with wide-ranging properties. Phase I studies indicated greater tolerability of lenalidomide in children compared with adults and a potential dose-response effect. PATIENTS AND METHODS We performed a phase II trial of lenalidomide in children with pilocytic astrocytomas and optic pathway gliomas who failed initial therapy. Primary objectives included determination of objective response rate of children randomly assigned to regimen A, low-dose (20 mg/m 2 /dose), or regimen B, high-dose (115 mg/m 2 /dose) lenalidomide, and assessment for early progression. Secondary objectives included estimation of event-free survival, overall survival, incidence of toxic events, and assessment of plasma lenalidomide concentrations. Lenalidomide was administered once daily × 21 days of each 28-day cycle for each regimen. RESULTS Seventy-four eligible patients were enrolled (n = 37, each arm). The predefined activity level of interest was achieved for both arms. Four objective responses were observed in each arm, and the number of early progressors was low. Eighteen patients completed 26 cycles of therapy (regimen A, n = 12; regimen B, n = 6). The median number of cycles was 14 (range, 2-26) for regimen A and 11 for regimen B (range, 1-26). Of 74 eligible patients who received study drug, 30 required dose reduction for toxicity (regimen A, n = 6; regimen B, n = 24) and 16 discontinued because of toxicity (regimen A, n = 2; regimen B, n = 14). CONCLUSION Lenalidomide demonstrates a sufficient level of activity in children with low-grade glioma to warrant further exploration. Low-dose (20 mg/m 2 /dose administered once daily × 21 days of each 28-day cycle) lenalidomide appears to have better tolerability with comparable activity.
Endocrine Therapy for Primary and Secondary Prevention After Diagnosis of High-Risk Breast Lesions or Preinvasive Breast Cancer
Authors: Alison Laws, Rinaa S. Punglia
Journal: Journal of Clinical Oncology (2023)

The Oncology Grand Rounds series is designed to place original reports published in the Journal into clinical context. A case presentation is followed by a description of diagnostic and management challenges, a review of the relevant literature, and a summary of the authors' suggested management approaches. The goal of this series is to help readers better understand how to apply the results of key studies, including those published in Journal of Clinical Oncology, to patients seen in their own clinical practice.Patients with high-risk breast lesions (HRLs) or preinvasive breast cancers face an elevated risk of future breast cancer diagnoses. Endocrine therapy in this setting reduces the risk of a future diagnosis but does not confer improved survival, thus the side effects of primary/secondary prevention must be considered relative to the benefits. Here, we discuss the available chemoprevention regimens for patients with HRLs and considerations for selecting a regimen, as well as the decision making surrounding use of adjuvant endocrine therapy for patients with ductal carcinoma in situ (DCIS). For patients with HRLs, available chemoprevention regimens differ by menopausal status, including tamoxifen 20 mg once daily for 5 years and more recently tamoxifen 5 mg once daily for 3 years in both premenopausal and postmenopausal women as well as raloxifene or aromatase inhibitors for postmenopausal women. We recommend a shared decision-making approach with attention to patient preferences related to risk tolerance and side-effect profiles. Low-dose tamoxifen appears to be a particularly favorable choice that is well tolerated, without risk of serious adverse events and offers comparable risk reduction to other regimens. For DCIS, the benefit of endocrine therapy in addition to radiation is small, and appears to be driven mainly by a reduction in contralateral breast diagnoses or new breast cancers. A strategy that reduces the side-effect profile of chemoprevention such as low-dose tamoxifen may be especially appealing in the setting of secondary prevention.
In patients with chronic neuropathic pain, cannabinoids improve sleep and reduce pain vs. placebo
Authors: James Kim
Journal: Annals of Internal Medicine (2023)

Source Citation McParland AL, Bhatia A, Matelski J, et al. Evaluating the impact of cannabinoids on sleep health and pain in patients with chronic neuropathic pain: a systematic review and meta-analysis of randomized controlled trials. Reg Anesth Pain Med. 2022;48:180-190. 36598058
Lipoprotein(a), Oxidized Phospholipids, and Coronary Artery Disease Severity and Outcomes
Authors: Thomas C. Gilliland, Yuxi Liu, Reza Mohebi, Hannah Miksenas, Sara Haidermota, Megan Wong, Xingdi Hu, Joaquim Rosado Cristino, Auris Browne, Jorge Plutzky, Sotirios Tsimikas, James L. Januzzi, Pradeep Natarajan
Journal: Journal of the American College of Cardiology (2023)
Sex Difference in Outcomes of Acute Myocardial Infarction in Young Patients
Authors: Mitsuaki Sawano, Yuan Lu, César Caraballo, Shiwani Mahajan, Rachel Dreyer, Judith H. Lichtman, Gail D’Onofrio, Erica Spatz, Rohan Khera, Oyere Onuma, Karthik Murugiah, John A. Spertus, Harlan M. Krumholz
Journal: Journal of the American College of Cardiology (2023)
1-Year Outcomes of Transcatheter Tricuspid Valve Repair
Authors: Susheel K. Kodali, Rebecca T. Hahn, Charles J. Davidson, Akhil Narang, Adam Greenbaum, Patrick Gleason, Samir Kapadia, Rhonda Miyasaka, Firas Zahr, Scott Chadderdon, Robert L. Smith, Paul Grayburn, Robert M. Kipperman, Leo Marcoff, Brian Whisenant, Mike Gonzales, Raj Makkar, Moody Makar, William O’Neill, Dee Dee Wang, William A. Gray, Sandra Abramson, James Hermiller, Lucas Mitchel, D. Scott Lim, Dale Fowler, Mathew Williams, Sorin V. Pislaru, Abdellaziz Dahou, Michael J. Mack, Martin B. Leon, Mackram F. Eleid
Journal: Journal of the American College of Cardiology (2023)
Pharmacological Regulation of Endoplasmic Reticulum Structure and Calcium Dynamics: Importance for Neurodegenerative Diseases
Authors: Ilmari Parkkinen, Anna Their, Muhammad Yasir Asghar, Sreesha Sree, Eija Jokitalo, Mikko Airavaara
Journal: Pharmacological Reviews (2023)

The endoplasmic reticulum (ER) is the largest organelle of the cell, composed of a continuous network of sheets and tubules, and is involved in protein, calcium (Ca<sup>2+</sup>) and lipid homeostasis. In neurons, the ER extends throughout the cell, both somal and axodendritic compartments, and is highly important for neuronal functions. A third of the proteome of a cell, secreted and membrane-bound proteins, are processed within the ER lumen and most of these proteins are vital for neuronal activity. The brain itself is high in lipid content and many structural lipids are produced, in part, by the ER. Cholesterol and steroid synthesis are strictly regulated in the ER of the blood-brain barrier protected brain cells. The high Ca<sup>2+</sup> level in the ER lumen and low cytosolic concentration is needed for Ca<sup>2+</sup>-based intracellular signaling, also for synaptic signaling and Ca<sup>2+</sup> waves, as well as preparing proteins for correct folding in the presence of high Ca<sup>2+</sup> concentrations to cope with the high concentrations of extracellular milieu. Particularly, ER Ca<sup>2+ </sup>is controlled in axodendritic areas for proper neurito- and synaptogenesis and synaptic plasticity and remodeling. In this review, we cover the physiological functions of the neuronal ER and discuss it in context of common neurodegenerative diseases focusing on pharmacological regulation of ER Ca<sup>2+</sup>. Furthermore, we postulate that heterogeneity of the ER, its protein folding capacity and ensuring Ca<sup>2+</sup> regulation is a crucial factor for the aging and selective vulnerability of neurons in various neurodegenerative diseases. <b>Significance Statement</b> ER Ca<sup>2+</sup> regulators are promising therapeutic targets for degenerative diseases for which efficacious drug therapies do not exist. The use of pharmacological probes targeting maintenance and restoration of ER Ca<sup>2+</sup> can provide restoration of protein homeostasis, e.g. folding of complex plasma membrane signalling receptors and slow down the degeneration process of neurons.
Bioinks for Space Missions: The Influence of Long‐Term Storage of Alginate‐Methylcellulose‐Based Bioinks on Printability as well as Cell Viability and Function
Authors: Johannes Windisch, Olena Reinhardt, Sarah Duin, Kathleen Schütz, Nuria Juliana Novoa Rodriguez, Suihong Liu, Anja Lode, Michael Gelinsky
Journal: Advanced Healthcare Materials (2023)

Bioprinting is considered a key technology for future space missions and is currently being established on the International Space Station (ISS). With the aim to perform bioink production as a critical and resource-consuming preparatory step already on Earth and transport a bioink cartridge "ready to use" to the ISS, the storability of bioinks is investigated. Hydrogel blends based on alginate and methylcellulose are laden with either green microalgae of the species Chlorella vulgaris or with different human cell lines including immortilized human mesenchymal stem cells, SaOS-2 and HepG2, as well as with primary human dental pulp stem cells. The bioinks are filled into printing cartridges and stored at 4°C for up to four weeks. Printability of the bioinks is maintained after storage. Viability and function of the cells embedded in constructs bioprinted from the stored bioinks are investigated during subsequent cultivation: The microalgae survive the storage period very well and show no loss of growth and functionality, however a significant decrease is visible for human cells, varying between the different cell types. The study demonstrates that storage of bioinks is in principle possible and is a promising starting point for future research, making complex printing processes more effective and reproducible.
Single-nucleus RNA sequencing of human pancreatic islets identifies novel gene sets and distinguishes β-cell subpopulations with dynamic transcriptome profiles
Authors: Randy B. Kang, Yansui Li, Carolina Rosselot, Tuo Zhang, Mustafa Siddiq, Prashant Rajbhandari, Andrew F. Stewart, Donald K. Scott, Adolfo Garcia-Ocana, Geming Lu
Journal: Genome Medicine (2023)

Abstract Background Single-cell RNA sequencing (scRNA-seq) provides valuable insights into human islet cell types and their corresponding stable gene expression profiles. However, this approach requires cell dissociation that complicates its utility in vivo. On the other hand, single-nucleus RNA sequencing (snRNA-seq) has compatibility with frozen samples, elimination of dissociation-induced transcriptional stress responses, and affords enhanced information from intronic sequences that can be leveraged to identify pre-mRNA transcripts. Methods We obtained nuclear preparations from fresh human islet cells and generated snRNA-seq datasets. We compared these datasets to scRNA-seq output obtained from human islet cells from the same donor. We employed snRNA-seq to obtain the transcriptomic profile of human islets engrafted in immunodeficient mice. In both analyses, we included the intronic reads in the snRNA-seq data with the GRCh38-2020-A library. Results First, snRNA-seq analysis shows that the top four differentially and selectively expressed genes in human islet endocrine cells in vitro and in vivo are not the canonical genes but a new set of non-canonical gene markers including ZNF385D , TRPM3 , LRFN2 , PLUT (β-cells); PTPRT , FAP , PDK4 , LOXL4 (α-cells); LRFN5 , ADARB2 , ERBB4 , KCNT2 (δ-cells); and CACNA2D3 , THSD7A , CNTNAP5 , RBFOX3 (γ-cells). Second, by integrating information from scRNA-seq and snRNA-seq of human islet cells, we distinguish three β-cell sub-clusters: an INS pre-mRNA cluster (β3), an intermediate INS mRNA cluster (β2), and an INS mRNA-rich cluster (β1). These display distinct gene expression patterns representing different biological dynamic states both in vitro and in vivo. Interestingly, the INS mRNA-rich cluster (β1) becomes the predominant sub-cluster in vivo. Conclusions In summary, snRNA-seq and pre-mRNA analysis of human islet cells can accurately identify human islet cell populations, subpopulations, and their dynamic transcriptome profile in vivo.
Time and event-specific deep learning for personalized risk assessment after cardiac perfusion imaging
Authors: Konrad Pieszko, Aakash D. Shanbhag, Ananya Singh, M. Timothy Hauser, Robert J. H. Miller, Joanna X. Liang, Manish Motwani, Jacek Kwieciński, Tali Sharir, Andrew J. Einstein, Mathews B. Fish, Terrence D. Ruddy, Philipp A. Kaufmann, Albert J. Sinusas, Edward J. Miller, Timothy M. Bateman, Sharmila Dorbala, Marcelo Di Carli, Daniel S. Berman, Damini Dey, Piotr J. Slomka
Journal: npj Digital Medicine (2023)

Abstract Standard clinical interpretation of myocardial perfusion imaging (MPI) has proven prognostic value for predicting major adverse cardiovascular events (MACE). However, personalizing predictions to a specific event type and time interval is more challenging. We demonstrate an explainable deep learning model that predicts the time-specific risk separately for all-cause death, acute coronary syndrome (ACS), and revascularization directly from MPI and 15 clinical features. We train and test the model internally using 10-fold hold-out cross-validation ( n = 20,418) and externally validate it in three separate sites ( n = 13,988) with MACE follow-ups for a median of 3.1 years (interquartile range [IQR]: 1.6, 3.6). We evaluate the model using the cumulative dynamic area under receiver operating curve (cAUC). The best model performance in the external cohort is observed for short-term prediction – in the first six months after the scan, mean cAUC for ACS and all-cause death reaches 0.76 (95% confidence interval [CI]: 0.75, 0.77) and 0.78 (95% CI: 0.78, 0.79), respectively. The model outperforms conventional perfusion abnormality measures at all time points for the prediction of death in both internal and external validations, with improvement increasing gradually over time. Individualized patient explanations are visualized using waterfall plots, which highlight the contribution degree and direction for each feature. This approach allows the derivation of individual event probability as a function of time as well as patient- and event-specific risk explanations that may help draw attention to modifiable risk factors. Such a method could help present post-scan risk assessments to the patient and foster shared decision-making.
Effect of an Herbal-Based Injection on 28-Day Mortality in Patients With Sepsis
Authors: Songqiao Liu, Chen Yao, Jianfeng Xie, Hong Liu, Hongliang Wang, Zhaofen Lin, Bingyu Qin, Difen Wang, Weihua Lu, Xiaochun Ma, Yan Liu, Ling Liu, Chi Zhang, Lei Xu, Ruiqiang Zheng, Feihu Zhou, Zhongmin Liu, Guoqiang Zhang, Lixin Zhou, Jian Liu, Aihua Fei, Guoxiu Zhang, Yimin Zhu, Kejian Qian, Ruilan Wang, Yafeng Liang, Meili Duan, Dawei Wu, Rongqing Sun, Ying Wang, Xijing Zhang, Quan Cao, Mingshi Yang, Minggen Jin, Yan Song, Ling Huang, Fachun Zhou, Dechang Chen, Qun Liang, Chuanyun Qian, Zhongzhi Tang, Zhong Zhang, Qiming Feng, Zhiyong Peng, Renhua Sun, Zhenju Song, Yunbo Sun, Yanfen Chai, Lihua Zhou, Chen Cheng, Li Li, Xiaoyan Yan, Junhua Zhang, Yingzi Huang, Fengmei Guo, Chuan Li, Yi Yang, Hongcai Shang, Haibo Qiu, Wenxue Liu, Meixia Shang, Jibin Han, Ming Li, Linhao Ma, Yunpeng Li, Yuanyi Liu, Tao Yu, Xin Li, Xing Lu, Qihong Chen, Yimin Yang, Yan Li, Weiguang Guo, Zhimin Dou, Chengjin Gao, Dahuan Li, Xiaotong Han, Qiang Shao, Yun Xie, Xiaoli Li, Jin Lin, Zhi Li, Min Gao, Yunxi Song, Binxiao Su, Yun Liu, Yue Peng, Qingsong Cui, Huichao Yu, Baocai Fu, Shihui Lin, Yanxia Huang, Xuedan Cao, Xiao Wang, Qing Fang, Ruolan Huang, Kaichao Yang, Ying Feng, Fangxiao Gong, Jun Yin, Shixia Cai, Shixin Li, Jingchao Wang, Wenke Zheng
Journal: JAMA Internal Medicine (2023)

Previous research has suggested that Xuebijing injection (XBJ), an herbal-based intravenous preparation, may reduce mortality among patients with sepsis.
Oncogenic Pathways Provide Clue to the Etiology of Human Mesial Temporal Lobe Epilepsy
Authors: Alica M. Goldman
Journal: JAMA Neurology (2023)

Our website uses cookies to enhance your experience. By continuing to use our site, or clicking "Continue," you are agreeing to our Cookie Policy | Continue JAMA Neurology HomeNew OnlineCurrent IssueFor Authors Podcast Journals JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry (1919-1959) JN Learning / CMESubscribeJobsInstitutions / LibrariansReprints & Permissions Terms of Use | Privacy Policy | Accessibility Statement 2023 American Medical Association. All Rights Reserved Search All JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Forum Archive JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry Input Search Term Sign In Individual Sign In Sign inCreate an Account Access through your institution Sign In Purchase Options: Buy this article Rent this article Subscribe to the JAMA Neurology journal
Metastatic Prostate Cancers with <i>BRCA2</i> versus <i>ATM</i> Mutations Exhibit Divergent Molecular Features and Clinical Outcomes
Authors: Justin Hwang, Xiaolei Shi, Andrew Elliott, Taylor E. Arnoff, Julie McGrath, Joanne Xiu, Phillip Walker, Hannah E. Bergom, Abderrahman Day, Shihab Ahmed, Sydney Tape, Allison Makovec, Atef Ali, Rami M. Shaker, Eamon Toye, Rachel Passow, John R. Lozada, Jinhua Wang, Emil Lou, Kent W. Mouw, Benedito A. Carneiro, Elisabeth I. Heath, Rana R. McKay, W. Michael Korn, Chadi Nabhan, Charles J. Ryan, Emmanuel S. Antonarakis
Journal: Clinical Cancer Research (2023)

In patients with metastatic prostate cancer (mPC), ATM and BRCA2 mutations dictate differences in PARPi inhibitor response and other therapies. We interrogated the molecular features of ATM- and BRCA2-mutated mPC to explain the divergent clinical outcomes and inform future treatment decisions. We examined a novel set of 1,187 mPCs after excluding microsatellite-instable (MSI) tumors. We stratified these based on ATM (n = 88) or BRCA2 (n = 98) mutations. As control groups, mPCs with mutations in 12 other homologous recombination repair (HRR) genes were considered non-BRCA2/ATM HRR-deficient (HRDother, n = 193), whereas lack of any HRR mutations were considered HRR-proficient (HRP; n = 808). Gene expression analyses were performed using Limma. Real-world overall survival was determined from insurance claims data. In noncastrate mPCs, only BRCA2-mutated mPCs exhibited worse clinical outcomes to AR-targeted therapies. In castrate mPCs, both ATM and BRCA2 mutations exhibited worse clinical outcomes to AR-targeted therapies. ATM-mutated mPCs had reduced TP53 mutations and harbored coamplification of 11q13 genes, including CCND1 and genes in the FGF family. BRCA2-mutated tumors showed elevated genomic loss-of-heterozygosity scores and were often tumor mutational burden high. BRCA2-mutated mPCs had upregulation of cell-cycle genes and were enriched in cell-cycle signaling programs. This was distinct from ATM-mutated tumors. Tumoral ATM and BRCA2 mutations are associated with differential clinical outcomes when patients are stratified by treatments, including hormonal or taxane therapies. ATM- and BRCA2-mutated tumors exhibited differences in co-occurring molecular features. These unique molecular features may inform therapeutic decisions and development of novel therapies.